The advantage of ET-traps over ET antagonists is that we are not completely blocking the actions of ET-1, which of course are essential to normal physiology. With the ET-traps, we are merely (potently) binding and sequestering pathologically elevated levels of ET-1, without completely blocking ET-1 function.
The binding affinity of our ET-traps is in the pico molar range, which is much higher than ERAs (that are currently in clinical use). Furthermore, the dissociation of our ET-traps once bound to ET-1 is very slow. This would aid the agenda of binding (excess) ET-1 and excreting it out of the body.
We did not detect any toxicology with the ET-traps in our in vitro and in vivo work done in the diabetes disease space. Please note, lowering the dosage of the antagonist (inhibitor drug) or the number of days administered per week, might help mitigate the side effects but a lower dose of the inhibitor drug may mean lower efficacy and therefore less symptom relief.
Fc-fusion proteins (FFPs), which are our ET-traps, are also beneficial over the more common 'therapeutic antibodies' for different reasons. FFPs have a longer serum half-life. Therefore, FFPs persist longer to bind their targets and have their therapeutic effects. This means (and importantly so) that patient dosing is reduced and patients need to take the therapy less often. Furthermore, FFPs can be modulated more easily so that the therapy does not elicit any negative immune reaction. In fact, the study by Ying et al. (2012) describes how a Fc-fusion (as are the ET-traps) is not immunogenic. This is again very important when developing a therapeutic. The study by Chames et al. (2009) discusses further the limitations of therapeutic antibodies.
Finally, a simple economic/financial comparison states how the TNF -alpha FFP has roughly 7.6 billion dollars per year sales - close to a billion higher than the most successful therapeutic antibodies. These figures truly give the value of Fc-based therapeutics.
The ET-traps of course are FFPs and given the positive in vitro and in vivo studies, may provide a successful alternative to antibodies and a potential therapy for diabetes (and possibly beyond).